Leachman appeared in many live television broadcasts in the 1950s, including such programs as Suspense and Studio One. In addition she was cast as the adoptive mother of "Timmy" (Jon Provost) in the 4th season of "Lassie", and was not happy in the role. She was also one of the Raisonette Girls in the 1960s.[citation needed] She made her feature film debut as an extra in the 1947 film Carnegie Hall, but had her first real role in Robert Aldrich's film noir classic Kiss Me Deadly,[10] released in 1955. Leachman was several months pregnant during the filming, and appears in one scene running down a darkened highway wearing only a trenchcoat. A year later she appeared opposite Paul Newman and Lee Marvin in The Rack (1956). She appeared with Newman again, in a brief role as a prostitute in Butch Cassidy and the Sundance Kid (1969). She also appeared as "Judy" in Season one, Episode 2 of the TV series Adam-12.

She continued to work mainly in television, with appearances in Rawhide and in The Twilight Zone episode It's a Good Life. During this period, Leachman notably appeared on the popular anthology Alfred Hitchcock Presents in an episode entitled "Premonition" opposite John Forsythe. Later in the decade, Leachman appeared as Ruth Martin, Timmy's adoptive mom, in the last half of season four (1957) of Lassie. Jon Provost ("Timmy Martin") said, "Cloris did not feel particularly challenged by the role. Basically, when she realized that all she'd be doing was baking cookies, she wanted out."[11] She was replaced by June Lockhart in 1959. In 1959, she appeared in an episode of One Step Beyond titled "The Dark Room", where she portrayed an American photographer living in Paris. In 1960 she played Marilyn Parker, the roommate of Janice Rule's character, Elena Nardos, in the Checkmate episode The Mask of Vengeance. In 1966 she guest starred on Perry Mason as Gloria Shine in "The Case of the Crafty Kidnapper." In late 1970, Leachman starred on one episode of That Girl as Don Hollinger's sister, "Sandy".

Leachman has also won a record-setting eight primetime and one daytime Emmy Awards and been nominated more than 20 times for her work in television over the years, most notably as the character of neighbor/landlady/nosy friend Phyllis Lindstrom on The Mary Tyler Moore Show. The character was a recurring character on the program for five years and was subsequently featured in a spinoff series, Phyllis (1975–1977), for which Leachman garnered a Golden Globe award. The series ran for two seasons. Its cancellation was partly due to the deaths of three regular or recurring cast members during its brief run: Barbara Colby, Judith Lowry and Burt Mustin.

She has voice-acted in numerous animated films, including My Little Pony: The Movie as the evil witch mother from the Volcano of Gloom, The Iron Giant, and most notably as the voice of the cantankerous sky pirate Dola in Hayao Miyazaki's 1986 feature Castle in the Sky. Dubbed by Disney in 1998, Leachman's performance in this film received nearly unanimous praise. Leachman played embittered, greedy, Slavic Canadian "Grandma Ida" on the Fox sitcom Malcolm in the Middle, for which she won two Emmy Awards, both for Outstanding Guest Actress in a Comedy Series (once in 2002, then again in 2006). She was nominated for playing that same character for six consecutive years.

In 1989, Leachman starred on Brooks' short-lived NBC sitcom The Nutt House[19] in dual roles as head hotel housekeeper Mrs. Frick (a variation of the Frau Blücher character) and Mrs. Nutt, the senile owner of the hotel (who was only featured in the 2-part pilot).

She auditioned for a chance to revive her role from Young Frankenstein in the 2007 Broadway production opposite Megan Mullally (replacing formerly cast Kristin Chenoweth) and Roger Bart. However, Andrea Martin was cast in the role. Mel Brooks was quoted as saying that Leachman, at 81, was too old for the role. "We don't want her to die on stage", he told columnist Army Archerd, at which Leachman took umbrage.[20] However, due to Leachman's success on Dancing with the Stars, Brooks reportedly asked her to reprise her role as Frau Blücher in the Broadway production of Young Frankenstein after Beth Leavel, who had succeeded Martin.[21][22] The Broadway production closed before this could be realized.

From 1953 to 1979, Leachman was married to Hollywood impresario George Englund. Leachman's former mother-in-law was character actress Mabel Albertson, best known for playing Samantha Stevens' bewildered and frustrated mother-in-law on Bewitched. The marriage produced five children, four sons and one daughter: Bryan (died 1986), Morgan, Adam, Dinah and George. Some of them are in show business. Her son Morgan played Dylan on Guiding Light throughout the 1980s and early 1990s.

She called herself an agnostic in an interview with Grandparents magazine.[23] In 2012, Leachman said she was an atheist.[24]

The Englunds were Bel Air neighbors of Judy Garland and Sid Luft, and of their children, Lorna and Joey Luft, during the early 1960s. Lorna Luft states in her memoir Me and My Shadows: A Family Memoir that Leachman was "the kind of mom I'd only seen on TV". Knowing of the turmoil at the Garland home but never mentioning it, Leachman prepared meals for Judy's children and made them feel welcome whenever they needed a place to stay.

Leachman was also a friend of Marlon Brando, whom she met while studying under Elia Kazan in the 1950s. She introduced him to her husband, who became close to Brando as well, directing him in The Ugly American and writing a memoir about their friendship called Marlon Brando: The Way It's Never Been Done Before (2005).[25]

In a parody of the famous Demi MooreVanity Fair magazine cover photo, Leachman posed "au naturel" on the cover of Alternative Medicine Digest (issue 15, 1997) body-painted with images of fruit. A vegetarian, Leachman also posed clad only in lettuce for a 2009 PETA advertisement.[26] Leachman also starred in a comedic 2013 spay and neuter ad for PETA, opening a condom wrapper with her teeth.[27]

Leachman's autobiography Cloris: My Autobiography[28] was published in March 2009. She wrote the bestselling book with her former husband, George Englund.

Leachman's granddaughter, Anabel Englund, is a singer.[29] In addition to Anabel, Cloris has five other grandchildren - Portia, Skye, Arielle, Jackson, Hallelujah, and one great-grandson Braden.